title: ALK amplification and protein expression predict inferior prognosis in neuroblastomas.
abstract: BACKGROUND
  ALK gene has been identified as a major neuroblastoma (NBL) predisposition gene. But ALK gene copy number and protein expression in ganglioneuroblastoma (GNBL) and ganglioneuroma (GN) are poorly described in the literature. Furthermore, there are controversies on the correlation between ALK protein expression and clinical outcome in NBL.
  
  
  METHODS
  We evaluated MYCN/ALK gene copy number by fluorescence in situ hybridization (FISH) and detected ALK protein expression by immunohistochemistry (IHC) in 188 NBL, 52 GNBL and 6 GN samples and analyzed their association with clinical outcome of the patients.
  
  
  RESULTS
  Although ALK gene copy number increase is a recurrent genetic aberration of neuroblastic tumors (NTs) (39.1%, 96/246), ALK amplification was only present in three NBLs (1.2%, 3/246). The frequency of ALK positivity in NBL (50.5%, 51/101) was significantly higher than in GNBL (22.6%, 7/31) and in GN (0.0%, 0/4) (P<0.05). In addition, ALK positivity also significantly correlates with MYCN/ALK gene copy number increases (P<0.05). Kaplan-Meier survival analysis indicated that MYCN/ALK amplification is correlated with decreased overall survival in NBL. A better prognosis trend was observed in patients with MYCN/ALK gain tumors compared with those with MYCN/ALK normal tumors. Furthermore, ALK positivity significantly correlated with inferior survival in NBL (P=0.044).
  
  
  CONCLUSIONS
  ALK positivity in NTs correlated with advanced tumor types and MYCN/ALK gene copy number increases. ALK positivity predicts inferior prognosis in NBL and IHC is a simplified strategy to screen ALK positivity in clinical practice.
authors.affiliation: Department of Pathology, Basic Medical College, Capital Medical University, Beijing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.forename: Chunju
authors.initials: C
authors.lastname: Zhou
authors.forename: Qinnuan
authors.initials: Q
authors.lastname: Sun
authors.forename: Rongqin
authors.initials: R
authors.lastname: Cai
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Daye
authors.initials: D
authors.lastname: Wang
authors.forename: Liping
authors.initials: L
authors.lastname: Gong
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002648:Child; D002675:Child, Preschool; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; FISH; IHC; MYCN; NTs